[7] The Wangkangurru people lived in the Simpson Desert using hand-dug wells called mikiri from long before European colonization until the Federation Drought.

In January 1886, surveyor David Lindsay ventured into the desert from the western edge, in the process discovering and documenting, with the help of a Wangkangurru Aboriginal man, 9 native wells, and travelling as far east as the Queensland/Northern Territory border.

Beer ran 420 km across the desert in 6.5 days, starting at Alka Seltzer Bore, South Australia and finishing at Birdsville, Queensland.

[13][14][15] In 1984, Dennis Bartel was the first white man to successfully walk solo and unsupported west-to-east across the Simpson,[16] 390 km in 24 days, relying on old Aboriginal wells for water.

Starting at Bedourie in Queensland, he walked solo and unsupported, towing all his equipment, food, and water in a two-wheeled cart to Old Andado homestead.

[17][18] Also in 2008, Belgian Louis-Philippe Loncke became the first non-indigenous person to complete a north–south crossing of the desert on foot, unsupported, and through the geographical centre.

[19][20][21] In 2016, explorer Sebastian Copeland and partner Mark George completed the longest unsupported latitudinal crossing (west-to-east across the dunes) of the Simpson[22] They linked the Madigan Line, Colson Track and French Line for the first time, walking from Old Andado homestead to Birdsville, a distance of 650 km (404 miles) in 26 days.

The Donohue Highway is an unpaved outback track passing from near Boulia towards the Northern Territory border in the north of the desert.

Before 1980, a section of the Commonwealth Railways Central Australian line passed along the western side of the Simpson Desert.

[26] The event features concerts and a Big Red Bash drag race across sand dunes to raise money for the Royal Flying Doctor Service of Australia.

In total, 17 million megalitres of water entered the State's western river systems, leading to Lake Eyre.

The Channel Country section of the ecoregion lies to the northeast of the desert proper around the towns of Bedourie and Windorah in Queensland, and consists of low hills covered with Mitchell grass cut through with rivers lined with coolabah trees.

Wildlife adapted to this hot, dry environment and seasonal flooding includes the water-holding frog (Litoria platycephala) and a number of reptiles that inhabit the desert grasses such as the perentie.

The birds that use these wetlands include the freckled duck (Stictonetta naevosa), musk duck (Biziura lobata), silver gull (Larus novaehollandiae), Australian pelican (Pelecanus conspicillatus), great egret (Ardea alba), glossy ibis (Plegadis falcinellus), and banded stilt (Cladorhynchus leucocephalus).

Also, the mound springs of the Great Artesian Basin are important habitat for a number of plants, fish, snails, and other invertebrates.

Native vegetation is largely intact as the desert is uninhabitable, so habitats are not threatened by agriculture, but are damaged by introduced species, particularly rabbits and feral camels.

The only human activity in the desert proper has been the construction of the gas pipelines, while the country on its fringes has been used for cattle grazing and contains towns such as Innamincka.

[35] The extensive dunefields of the Simpson Desert display a range of colours from brilliant white to dark red, and include pinks and oranges.